PD-1 blockade does not enhance alloimmunization after allogeneic dendritic cell vaccination in cancer patients

Background: Blocking programmed cell death protein 1 (PD-1) has become a standard cancer immunotherapy, increasingly used in kidney, liver, or heart transplant recipients who develop skin cancer or hepatocellular carcinoma, despite the increased risk of graft failure or rejection. The mechanism of action of PD-1 blockade relies on stimulating CD8+ T cell activity, but its impact on humoral immunity in general and on alloimmunization in particular remains uncertain. Objective: The aim of this study was to investigate the impact on anti-PD-1 treatment on alloimmunization. Methods: The effect of anti-PD-1 treatment on the generation of anti-HLA (Human Leucocyte Antigen) antibodies was investigated in 72 patients with non-small cell lung cancer vaccinated with an allogeneic plasmacytoid dendritic cell line (PDC*line; six weekly injections), with or without pembrolizumab administered every three weeks. The kinetics and functionality of the anti-HLA generated were analyzed. Results: The results show that 51.4% of the patients developed anti-HLA antibodies, primarily dependent on the vaccine dose. In 60% of cases, the antibody response appeared after the sixth injection, peaked after one month, and then gradually declined over two years. Anti-HLA class II antibodies appeared earlier than class I antibodies. Functional assays demonstrated complement-dependent cytotoxicity against allogeneic B lymphocytes and PDC*line cells in the serum of some patients, with no difference related to treatment. PD-1 blockade did not alter the magnitude, kinetics, or cytotoxic potential of the vaccine-induced humoral response. Conclusion: These results indicate that, during allogeneic human vaccination, PD-1 signaling exerts a limited effect on antibody production and effector function, suggesting a more complex regulatory role in humoral immunity than previously thought.